The present invention relates to pharmaceutical formulations and methods for application of immunomodifying imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amine, thiazolo- and oxazolo-quinolinamines and pyridinamines, imidazonaphthyridine and tetrahydroimidazonaphthyridine amines to a mucosal surface. In one embodiment, the invention provides formulations and methods which are particularly advantageous for topical application to the cervix for treatment of cervical conditions such as cervical dysplasias including dysplasia associated with human papillomavirus (HPV).
Many imidazoquinoline amine, imidazopyridine amine, 6,7-fused cycloalkylimidazopyridine amine, 1,2-bridged imidazoquinoline amine, thiazolo- and oxazolo-quinolinamines and pyridinamines, imidazonaphthyridine and tetrahydroimidazonaphthyridine amine compounds have demonstrated potent immunostimulating, antiviral and antitumor (including anticancer) activity, and have also been shown to be useful as vaccine adjuvants to enhance protective immune system response to vaccines. These compounds are hereinafter sometimes collectively referred to as the xe2x80x9cIRMxe2x80x9d (immune response modifier) compounds of the invention. Such compounds are disclosed in, for example, U.S. Pat. Nos. 4,689,338; 5,389,640, 5,268,376, 4,929,624, 5,266,575, 5,352,784, 5,494,916, 5,482,936, 5,346,905, 5,395,937, 5,238,944, 5,525,612, WO99/29693 and U.S. Ser. No. 09/361,544 wherein their immunostimulating, antiviral and antitumor activities are discussed in detail, and certain specific diseases are identified as being susceptible to treatment therewith, including basal cell carcinoma, eczema, essential thrombocythaemia, hepatitis B, multiple sclerosis, neoplastic diseases, psoriasis, rheumatoid arthritis, type I herpes simplex, type II herpes simplex, and warts. One of these IRM compounds, known as imiquimod, has been commercialized in a topical formulation, Aldara(trademark), for the treatment of anogenital warts associated with human papillomavirus.
The mechanism for the antiviral and antitumor activity of these IRM compounds is thought to be due in substantial part to enhancement of the immune response due to induction of various important cytokines (e.g., interferons, interleukins, tumor necrosis factor, etc.). Such compounds have been shown to stimulate a rapid release of certain monocyte/macrophage-derived cytokines and are also capable of stimulating B cells to secrete antibodies which play an important role in these IRM compounds"" antiviral and antitumor activities. One of the predominant immunostimulating responses to these compounds is the induction of interferon (IFN)-xcex1 production, which is believed to be very important in the acute antiviral and antitumor activities seen. Moreover, up regulation of other cytokines such as, for example, tumor necrosis factor (TNF), IL-1 and IL-6 also have potentially beneficial activities and are believed to contribute to the antiviral and antitumor properties of these compounds.
Although some of the beneficial effects of IRM""s are known, the ability to provide therapeutic benefit via topical application of an IRM for treatment of a particular condition at a particular location may be hindered due to tissue irritation, formulation wash away, poor permeation or undesired systemic delivery of the topically applied compound. Accordingly, there is a need for new methods and formulations to provide the greatest therapeutic benefit from this class of compounds.
It will be appreciated that at several locations throughout the specification, guidance is provided through lists of examples. In each instance, the recited list serves only as a representative group; it is not meant that the list is exclusive.
The present disclosure provides pharmaceutical formulations containing immune response modifier (xe2x80x9cIRMxe2x80x9d) compounds and methods for treatment of conditions associated with a mucosal surface. The methods and formulations of the invention may be particularly advantageous for treatment of cervical conditions such as cervical dysplasias including cervical intraepithelial neoplasia.
Particularly preferred IRM compounds suitable for the pharmaceutical formulations of the invention include 4-amino-2-ethoxymethyl-xcex1,xcex1-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol and 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (known as imiquimod).
The IRMs can be formulated for application to a mucosal membrane, particularly the cervical mucosa.